In the U.S., bladder cancer is the fourth most common type of cancer in men and the ninth most common cancer in women. Smoking and age are the main known risk factors, with nearly 90% of patients over age of 55. In 2011, it is estimated that there will be 69,250 new cases in the U.S., resulting in 14,990 deaths. Non-muscle invasive bladder cancer (NMIBC) begins and stays in the cells lining the bladder without growing into the deeper main muscle layer of the bladder, and accounts for the majority (70-80%) of patients diagnosed with bladder cancer (stages Ta, T1, or CIS). Approximately 30% of patients present with muscle-invasive disease (stages T2-T4). Bladder cancer has the highest recurrence rate of any malignancy. Although NMIBC is a relatively benign disease, it recurs in 50-70% of patients, of which 10-20% would eventually progress to high-grade muscle-invasive disease. Furthermore, the disease is also characterized by having a large pool of patients who have been previously diagnosed and are still undergoing treatment for unresolved tumors; more than 1 million patients in the U.S. and Europe are estimated to be affected by the disease.
The high-grade muscle invasive disease is typically treated with radical cystectomy or a combination of radiation therapy and chemotherapy. However, even after treatment the tumor usually remains and patients are at risk of tumor progression, leading to a shortened life expectancy or death from metastatic disease. Approximately 350,000 patients in the U.S. and EU are currently undergoing treatment for unresolved tumors.
NMIBC is typically treated with intravesicular BCG, which elicits a nonspecific local immune response against the tumor cells. BCG elicits a nonspecific massive local inflammatory reaction in the bladder wall, and elevated appearance of cytokines can be detected in the urine of BCG-treated patients. BCG is internalized by antigen-presenting cells, such as macrophages, but also by urothelial tumor cells, which result in an altered gene expression of these cells. Additionally, none of the available chemotherapeutic agents, including gemcitabine, cisplatin, and valrubicin, that are currently explored in clinical trials for treating bladder cancer are targeted therapeutics.
Sirolimus (INN/USAN), also known as rapamycin, is an immunosuppressant drug used to prevent rejection in organ transplantation; it is especially useful in kidney transplants. It prevents activation of T cells and B cells by inhibiting their response to interleukin-2 (IL-2). The mode of action of sirolimus is to bind the cytosolic protein FK-binding protein 12 (FKBP12), and the sirolimus-FKBP12 complex in turn inhibits the mammalian target of sirolimus (mTOR) pathway by directly binding the mTOR Complex1 (mTORC1).
Albumin-based nanoparticle compositions have been developed as a drug delivery system for delivering substantially water insoluble drugs. See, for example, U.S. Pat. Nos. 5,916,596; 6,506,405; 6,749,868, and 6,537,579, 7,820,788, and 7,923,536. Abraxane®, an albumin stabilized nanoparticle formulation of paclitaxel, was approved in the United States in 2005 and subsequently in various other countries for treating metastatic breast cancer. It was recently approved for treating non-small cell lung cancer in the United States, and has also shown therapeutic efficacy in various clinical trials for treating difficult-to-treat cancers such as bladder cancer and melanoma. Albumin derived from human blood has been used for the manufacture of Abraxane® as well as various other albumin-based nanoparticle compositions.
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